1. Field of the Invention
The present invention relates in general to the field of transdermal and dermal drug delivery by using formulations of said compositions including chemical penetrants molecules, polar solvents, cream base, antioxidants and therapeutic pharmaceutical or cosmetic active agents for treating various diseases, pains, skin conditions and other neurological and non-neurological maladies.
In particular, the present invention relates to the formulation of a cream, gel, lotion, patch or spray (transdermal carrier) with a Chemical Penetration Enhancer (CPE) comprising of a mixture of cetylated fatty acid esters and polar solvents (Cetylated Fatty Ester Penetrant Complex; CFEP-complex), in predetermined combinations and with desired pharmaceutical and cosmeceutical agents, which when added together in the vehicle carrier and administered to the skin of an individual has the effect of carrying the therapeutic substance across the skin barrier and enabling the dermal and/or systemic beneficial effects of the transported molecules.
2. General Discussion and Related Art
Transdermal Drug Delivery (TDD) and Approaches to Permeation Most transdermal drug delivery inventions can be divided into system innovations and formulation innovations. The system innovations involve mainly technologies that use either mechanical or various energy sources to increase drug flux across the skin. Formulation innovations involve chemical systems that either attempt by various alterations at the molecular level to increase the flux of drug across the skin or improve performance and stability of a Transdermal Delivery (TDD) system.
Gels, creams, lotions, and sprays, for which many chemical system innovations have been developed, have a long history in topical and local dermal applications. There are many advantages for the mode of application: convenience of application, numerous potential sites of application, demonstrated dosing potential in multiple formulations with reasonable safety, and a potentially larger surface area for application than a transdermal patch.
The major steps in transdermal permeation are: 1) partitioning of the permeant in the outermost layer of the stratum corneum (with keratin-filled corneocytes anchored in a lipophillic matrix), 2) diffusion after partitioning through the stratum corneum, then 3) further partitioning at the stratum corneum/viable epidermis junction as the permeant diffuses through the junction into viable tissue and 4) partitioning and diffusion through the dermal tissues into the capillaries. Further effects on the partitioning and diffusion processes are the binding of permeants to various elements (such as binding to keratin or drug receptors) of the skin (reservoir effect) and metabolic effects on the permeant that may occur during the process of permeation. By these latter effects permeants may become degraded or activated (i.e, prodrug converted to drug by activation metabolism).
By “transdermal” drug delivery is meant administration of a drug to the skin surface of an individual so that the drug passes through the skin tissue and into the individual's blood stream.
The term “topical administration” is used in its conventional sense to mean delivery of an active agent to a body surface such as the skin or mucosa, as in, for example, topical drug administration in the prevention or treatment of various skin disorders, the application of cosmetics and cosmeceuticals (including moisturizers, masks, sunscreens, etc.), and the like. Topical administration, in contrast to transdermal administration, provides a local rather than a systemic effect.
Similarly, when the term “transdermal” is used herein, as in “transdermal drug administration” and “transdermal drug delivery systems,” it is to be understood that unless explicitly indicated to the contrary, “topical” administration and systems are intended as well.
Advantages of transdermal delivery include: avoidance of first pass effects described for tablets and capsules; and problems associated with stomach irritation. In certain circumstances, it is desirable to deliver a therapeutic agent or cosmetic agent topically to the skin at a target site. Both transdermal and topical delivery devices rely on the adherence of a cream, gel, lotion, spray or a patch to the surface of the skin or other body surface.
Chemical Permeation Enhancers (CPE)
Approximately 450 chemicals are classified as Chemical Permeation Enhancers (CPE). CPEs are typically classified under (1) Water (2) Sulfoxide (3) Azone (4) Pyrrolidones (5) Fatty Acids (6) Alcohols, Fatty Alcohols and Glycols (7) Surfactants (8) Urea and (9) Essential Oils, Terpenes and Terpenoids.
Depending on their mechanism of action, CPEs can also be divided in 2 broad categories—either those that alter the structure of the skin lipids, thereby decreasing their resistance to diffusion (e.g., Polyethylene Glycol, alcohols and Menthol) or those that enhance the solubility of the diffusing drug within the skin.
CPEs may facilitate delivery by combinations of the following mechanisms: displacement of bound water, loosening of the corneocyte polymeric structure, extraction of lipids from the stratum corneum and inducing delamination of the stratum corneum osmotically, causing swelling and inducing channels to form in the matrix.
CPEs can increase entropy (As) in the lipid bilayers, thus reducing the skin barrier to diffusion, allowing topically applied drugs to diffuse through more easily. They operate in complex interacting ways to change the intercellular region of the horny layer of fluidization altering polarity, phase separation, or lipid extraction.
Innovations of the present invention address permeation of both lipophilic and hydrophilic compounds:
Lipophilic compounds partition into and penetrate the lipid domains of the stratum corneum. Hydrophilic compounds and ionized species require different approaches to penetration than that of uncharged lipophilic chemicals. Unlike lipophilic compounds, polar compounds demonstrate permeability coefficients that suggest independence of lipophilicity in order to penetrate. In general, permeability coefficients for ionized compounds are lower than coefficients for nonionized compounds because of higher water solubility. Further, permeability may show additional complexity when both ionized and nonionized species are simultaneously penetrating the skin (for example, partially ionized chemicals such as atropine, naproxen and salicylic acid).Fatty Acids in Transdermal Delivery
A wide variety of long-chain fatty acids, which have been used as CPEs, increase transdermal delivery; the most popular being oleic acid (C18 unsaturated), followed by linoleic acid (C18 polyunsaturated). Fatty acids effects on drug delivery to and through human skin can vary. It is relevant that many penetration enhancers contain saturated or unsaturated hydrocarbon chains and some structure-activity relationships have been drawn from the extensive studies.
Various analogs of fatty acids have been researched as penetration enhancers, for example diesters increased the permeation of NSAIDS through rat skin [Takahashi, K et al 2002 Drug Dev Ind Pharm 28:1225]. In addition, fatty acids have been shown to improve percutaneous absorption of, among others, estradiol, progesterone, acyclovir, 5-fluorouracil, and salicylic acid, which indicates that these CPEs can be used to promote delivery of both lipophilic and hydrophilic permeants. It is this property of facilitating both types of permeants that makes fatty acids desirable as enhancers. U.S. Pat. No. 4,940,586 discloses skin permeation enhancement due to fatty acid sucrose esters. U.S. Pat. No. 5,006,342 lists numerous fatty acid esters or fatty alcohol esters, for which the fatty acid/alcohol portion are about 8-22 carbon atoms. U.S. Pat. No. 4,863,970 describes a penetration-enhancing vehicle containing one or more cell-envelope disordering compounds such as oleic acid, oleyl alcohol (and others) in an inert diluent, such as water.
Extensive studies on a range of fatty acids and alcohols, sulfoxides, surfactants, and amides as enhancers for naloxone by Aungst and coworkers [Aungst, et al 1986 Int J pharm 33:2256; Aungst et al 1989 Pharm Res 6:244] showed that saturated acids with a chain length of C9-C12 increased the flux of the drug 40-fold, whereas unsaturated fatty acids required optimum chain length near C18: for example oleic acid and linoleic acid.
Related experiments have demonstrated that saturated alkyl chain lengths of around C10 to C12 attached to a polar head group yield the best promoters. Hydroxylated and esterified derivatives of various fatty acids, such as cis-9-octadecenoic acid (oleic acid), cis-(ricinoleic acid) and trans-(ricinaelaidic acid), have also been synthesized and studied for permeation enhancement of hydrocortisone and 5-FU in vitro, by using excised hairless mouse skin [Song et al 2001 Int J Pharm (amst) 212:153-160].
It is apparent from numerous literature reports that the fatty acid derivatives interact with and modify the lipid domains of the horny layer as would be expected for a long chain fatty acid with cis configuration. Spectroscopic investigations using deuterated oleic acid in human stratum corneum indicates that at a higher concentration, it can also exist as a separate phase within the bilayer lips [Takahashi, K et al 2002 Drug Dev Ind Pharm 28:1225]. The creation of such pools provides permeability defects within the intercellular domain thus facilitating penetration of hydrophilic permeants through the membrane.
Description of Cetylated Fatty Esters as CPEs in the Disclosed Invention
The present invention relies greatly on cetylation of the desired fatty acid esters to facilitate permeation and thus the delivery of the desired therapeutic molecule or molecules. The presence of the cetyl chain greatly increases the molecular size of the esterified molecules, as well as providing additional lipophilic characteristics due to the hydrocarbon chain. This portion of the CPE molecule presents the least disruption of the lipid matrices in the stratum corneum and facilitates penetration. A graphic depiction showing an example of an esterified fatty acid is shown below

Fatty acids that are alkanes with no unsaturated regions provide secondary structure that is straight and that can readily intercalate between membrane lipids with least disruption. Fatty acids with double bonding between carbons in a cis configuration introduce bending in the secondary structure that when intercalated in the membrane lipids, causes disruptions in the membrane configuration. Likewise, branching of the fatty acid carbon chain or with the introduction of cis-unsaturation, chain branching, or methyl or methoxy-groups along the fatty acid carbon chain can be utilized. These molecules intercalate within the lipid bilayers with several disruptions—rotating, vibrating, translocating, forming microcavities and increasing the free volume available for drug diffusion. Pooling may occur with formation of permeable pores that, for polar molecules, provide greater access to viable epidermis. This may be a critical step in allowing diffusion through the gel-like viscosity of the lipid matrix.
Background of Targeted Maladies
Testosterone Deficiency
Hypogonadism is a significant problem and these patients suffer from testosterone deficiency. In the United States there are an estimated 10 to 11 million patients who suffer from testosterone deficiency. Testosterone Replacement Therapy (TRT) has been around for a long time and there are various options available for TRT.
Intramuscular injections: These injections are given once every 10 to 14 days, and contain testosterone in various forms such as testosterone enanthronate, testosterone propionate, testosterone cypionate and testosterone undecanoate. Patients find these injections painful and uncomfortable and affective for up to 10 days
Oral Testosterone: Is not very effective and these oral compositions may contain mesteroline, testosterone undecanoate, methyltestosterone, and fuoxymesterene.
Transdermal Delivery:
Subcutaneous: This is not such a common method but pellets containing Testosterone are placed subcutaneously.
Transdermal: There are two main ways, one using a transdermal patch and the second using a gel. There are several of these products on the market such as Androgel (Unimed Pharmaceuticals), Testogel (Bayer Pharmaceuticals), Testim (Auxilium Pharmaceuticals) and Andractim (Laboratories Besins-Isvesco, France). All of these are 0.7% to 1% testosterone gels. This has to be applied everyday. The delivery mechanism of the gel resides in testosterone drying up on the skin and being absorbed by the skin continuously.
The current invention proposes to deliver these molecules transdermally using the CFEP carrier.
Urinary Incontinence UI: Urinary Incontinence UI affects about 15% of the population particularly women—most especially after women have had two-three children. An estimated 20-25% of the women over age 50 have UI. There are 17 million men and women in the USA suffering from UI. Out of the two most common treatments, oral Oxybutynin is more effective than oral Tolteridone, but the former carries more significant side effects. Although both molecules are effective in the treatment of UI, the associated side effects result in poor patient compliance with continuing the oral treatment. A major side effect is extreme drying of the mouth which in turn results in need to drink a lot of water and thus results in urge to void. Oxybutynin also enters the blood brain barrier and thus has been shown to have some cognitive impairment. Constipation, sweating and drowsiness are other side effects reported. Oxybutynin is metabolized very quickly in the liver and thus the side effects are less in orally administered Tolteridone but drying of mouth is common in both modalities. Patient compliance is ˜30% with oral Oxybutynin and around 40-50% with Tolteridone. There are 2 treatment options available: Oral tablets or Transdermal Patches
1. Oral Tablets: There are 2 compounds currently available worldwide and they are Oxybutynin and Tolterodone. Oxybutynin is a Muscarinic receptor antagonist. When patients take these formulations, they act on smooth muscles inhibiting acetylcholine thus increasing bladder capacity by reducing the number of motor impulses to void.
2. Oxybutynin Patches: Oxytrol is a transdermal patch available on the market manufactured by Watson Pharmaceuticals. This is effective and the side effects seen with orally administered Oxybutynin are minimized.
The current invention proposes to deliver these molecules transdermally using the CFEP carrier.
Musculoskeletal pain, joint pain and other types of inflammatory pain: Arthritis is a disease which affects approximately one in seven Americans, and which actually encompasses more than one hundred different diseases frequently having entirely different symptoms, causes, and known treatments.
Cetyl myristoleate has been used for treatment of rheumatoid arthritis (Diehl, U.S. Pat. No. 4,113,881) and osteoarthritis (Diehl, U.S. Pat. No. 5,569,676) [Hesslink et al. 2003, Kramer et al. 2004]. Other types of pain include repetitive strain injuries (a subcategory of Myofascial pain syndromes) tendonitis, bursitis, lower back pain, neck pain, fibromyalgia pain and headaches (Sharan D, et al. 2009, submitted for publication.
The current invention proposes to deliver these molecules transdermally using the CFEP carrier.
Neuropathic Pain (NP): Approximately 4 million individuals in the United States alone suffer from Neuropathic Pain (NP) such as pain seen in patients with diabetes (Diabetic peripheral neuropathy), Bell's palsy and Post Herpetic Neuropathies. Furthermore, NP response to traditional analgesics has been found to be relatively poor and oral treatments often do not provide instant pain relief as the drugs administered needs time to work on the targeted pain pathways.
Oral tablets containing methylcobalamin have been used in treating patients with Vitamin B12 deficiency, pernicious anemia and neuropathic pain in diabetics and other disorders. Vitamin B12 is absorbed very slowly and its positive effects are slow to act in patients with Diabetic Peripheral Neuropathy. Thus pain relief may be slower to attain. Sublingual methylcobalamin administration is a new approach for which there are claims for rapid absorption through the pores beneath the tongue. Sublingual administration is widely used by doctors in the treatment of Vitamin B 12 deficiency, pernicious anemia and neuropathic pain. Oral methylcobalamin is absorbed by passive diffusion at a rate of 1-2% of the ingested material. Food bound B12 malabsorbtion is common especially in older people. Cyanocobalamin is also administered using intravenous and nasal routes but the compliance is poor.
An alternative way to administer the methylcobalamin is through the transdermal route and in the form of a cream or gel or spray or a patch. There are several advantages of transdermal delivery as it avoids being metabolized in the liver, increases patient compliance, and most importantly the dosage used in oral formulations can be reduced significantly. US PTO#20080233180 (provisional) describes the delivery of methylcobalamin via skin patches using methylene and propylene glycol. Methylcobalamin molecule is large (MW 1355) and may be considered not possible to penetrate the skin, because only molecules less than 350 MW or lower can penetrate the skin. In our invention we have shown that CFEP carriers appears to facilitate penetration methylcobalamin rapidly. The current invention proposes to deliver these molecules transdermally using the CFEP carrier.
Pregabalin and gabapentin oral tablets or capsules have been used in the treatment of convulsions and seizures and more recently in treating neuropathic pain and fibromyalgia. The US FDA has approved a drug under the brand name of Lyrica marketed by Pfizer. Although an effective formulation the oral formulations are associated with adverse reactions such as drowsiness and dizziness in more than 10% of the patients. In addition a large number of patients report visual disturbance, lethargy, memory impairment, erectile dysfunction and weight gain. Oral Pregabalin is rapidly absorbed with bioavailability of more than 90%. Pregabalin greatly potentiates benzodiazepan and barbiturates and other depressants and may cause dependence and abuse. The current invention proposes to deliver pregabalin and gabapentin molecules transdermally using the CFEP carrier in order to obviate the dependence and maybe reduce the significant side effects.
Repetitive Strain Injuries (RSI): RSI is a multifactorial pain syndrome affecting the neck, upper back, shoulder, upper and lower arm, elbow, wrist or hand, or a combination of these areas, which leads either to impairment or to participation problems. The syndrome is characterized by disturbance in the balance between load and physical capacity, preceded by activities that involve repeated movements or prolonged periods spent with one or more of the relevant body parts in a fixed position as one of the presumed etiological factors. Typical manifestations include tightness, discomfort, stiffness, soreness, tingling, loss of strength and coordination in arms, pain in upper neck, back, lack of sleep due to pain and others. In general, RSI include more than 100 different kinds of disorders usually arising due to a combination of physical and psychosocial factors. These injuries vary from person to person in type and severity. An estimated 20-30% of software engineers and client service representatives suffer from these injuries. Several NSAIDS with or without physical therapy are used in treating such patients. Similarly a complex of fatty acid esters have been used in treating such pain transdermally (Sharan et al., 2009, submitted for publication). The current invention proposes to deliver these molecules transdermally using the CFEP carrier.
Hyperkeratosis and Xerosis: Otherwise known as cracked feet, it affects 20-30% of the normal population and at least 30% of patients who have chronic diabetes. Untreated, cracked feet in diabetics are prone to ulceration, which may get infected and in severe situations require amputation. Xerosis can be defined as dehydration of skin characterized by redness, dry scaling, and fine cracking much like the cracking of porcelain. Xerosis occurs most frequently on the extremities, especially the feet and legs. Hyperkeratosis is usually defined by monitoring the hypertrophy of the horny layer of the skin. This contributes to the flattened and raised borders noted in severity descriptions. Several alpha hydroxy acids have been used in the treatment of Xerosis. The current invention proposes to deliver these molecules transdermally using the CFEP carrier.
Epilepsy:
A great amount of empirical research has been conducted to treat the various subtypes of epilepsy. Status Epilepticus (SE) is typically treated with valproate, phenytoin, thiopentone, pentobarbital, propofol, isoflurane, felbamate, midazolam, diazepam, clobazam, folinic acid, pyridoxine, gabapentin, or vigabatrin. For refractory generalized convulsive status epilepticus, continuous intravenous midazolam infusion at 0.1-0.6 mg/kg/hr after a 0.2 mg/kg intravenous bolus is effective and has advantages over traditional therapies since it induces less hypotension and cardio-respiratory depression and can be easily titrated; cessation of seizures usually occurs before burst suppression is achieved on EEG.
Diazepam is commonly used as a first treatment for SE and acute seizures, and is restricted to patients with continuing convulsions or those having another convulsion during infusion of a maintenance medication. Lipid soluble Diazepam enters the brain rapidly, and provides an anticonvulsant effect shortly after administration. Although diazepam is a drug of choice for the management of refractory SE, the longer duration of action of lorazepam and clonazepam may favor the use of these latter two drugs.
Typically 10 mg of diazepam (0.15 mg/kg) is administered intravenously over a period of a few minutes. Diazepam administration can also be in a buccal or rectal formulation. Rectal and buccal formulations bypass metabolism in the liver and diazepam is in the system within 30 to 40 minutes. Compared to rectal and buccal administration, intramuscular and oral diazepam are metabolized slowly and is not used when acute seizure control is needed. The current invention proposes to deliver these molecules transdermally using the CFEP carrier.